The Role of Radioligand Therapy in Gastroenteropancreatic Neuroendocrine Tumors: An Italian Expert Opinion

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) comprise a heterogeneous group of clinically diverse tumors; their management is based on clinical characteristics. International guidelines recommend standard-dose somatostatin analogues (SSAs) as first-line treatment for advanced, low-grade G1 and "low" G2 NETs. No standard-of-care treatment is determined for "high" G2 and G3 NETs. Radioligand therapy (RLT) with [¹⁷⁷Lu]Lu-DOTA-TATE was authorized to treat well-differentiated (G1 and G2) unresectable or metastatic, somatostatin receptor (SSTR)-positive GEP-NETs, in progression after SSA. Recently published NETTER-2 is the first randomized clinical trial to demonstrate the efficacy and safety of [¹⁷⁷Lu]Lu-DOTA-TATE as first-line treatment in patients with newly diagnosed, advanced "high" G2 and G3 GEP-NETs. In February 2024, 13 scientific board members discussed RLT guidelines and treatment perspectives in patients with GEP-NETs based on NETTER-2 outcomes. In their opinion, NETTER-2 will impact first-line treatment choice in patients with G2 SSTR-positive GEP-NETs. RLT as first-line treatment could reduce tumor burden rather than maintain stable disease, except in patients who are highly symptomatic where chemotherapy should be considered. In patients with G3 SSTR-positive GEP-NETs, NETTER-2 strongly supports RLT as potential first-line treatment. RLT could also have a significant role in a perioperative setting for those cases with borderline resectable disease or advanced oligometastatic disease. The results of NETTER-2 confirm that therapy selection should be guided by symptoms, syndrome, and functional expression of SSTR within the tumor site(s) rather than GEP-NET histology and grading. Thus, the scientific board agreed that RLT should always be considered in SSTR-positive GEP-NETs. Graphical Abstract available for this article.